Bone Quality Sleuths: Uncovering Tissue-Level Mechanisms of Bone Fragility in Human Type 2 Diabetes

Commentary

Epidemiologic studies demonstrate that bone fragility is one of the many profound clinical consequences of type 2 diabetes mellitus (T2DM).^(1,2) This increased risk of fracture in T2DM persists even after controlling for potential confounding factors such as falls. Perhaps the most surprising revelation from large human cohort studies is that the elevated fracture incidence in T2DM occurs despite increased bone mineral density. Understanding the mechanisms responsible for bone fragility in people with T2DM could improve efforts to prevent fragility fractures, with identification and treatment of individuals at highest risk.

The increased bone fragility in T2DM patients, in spite of their elevated bone mass, highlights the importance of bone quality. Bone quality is a blanket term that encompasses the many properties of bone, other than bone mass, that influence its strength. It reflects bone geometry or microarchitecture, and the composition or organization of collagen and mineral, the major bone matrix constituents. Like bone mass, healthy bone quality is maintained by the coordinated action of osteoblasts, osteoclasts, and osteocytes, and it is susceptible to a host of disease processes including T2DM.⁽³⁾ Primarily using animal models, prior studies have attributed the poor bone quality in T2DM patients to factors including abnormal collagen crosslinking, microarchitecture, and matrix mineralization.^(4–7) However, the extent to which each of these mechanisms is responsible for bone fragility in human T2DM has been a major outstanding question.

The study by Hunt and colleagues⁽⁸⁾ in this issue of the JBMR bridges the gap between the epidemiologic findings of T2DM bone fragility and the experimental ones. Using human femoral neck cancellous bone from individuals with T2DM and nondiabetic controls, this study probes several aspects of bone quality using collagen crosslink analysis, FTIR, mechanical testing, and μCT. Although the group size of 31 to 34 in this study is tiny by the standards of large epidemiologic cohorts, it significantly exceeds the standard in a field where conclusions about human bone quality sometimes rely on a handful of specimens. The robust analyses of human bone quality and composition join published studies by Pritchard and colleagues⁽⁹⁾ and Karim and colleagues⁽¹⁰⁾ in advancing our understanding of the mechanisms of bone fragility in human diabetes. The results challenge the assumptions based on animal models. By performing regression analyses with their experimental data, the team sheds new light on this clinically relevant and scientifically perplexing problem, and draws some surprising but important conclusions.

Consistent with prior studies, this team observes T2DM-dependent differences in the organic and mineral constituents of bone matrix. The collagen in human T2DM bone matrix has elevated levels of the advanced glycation end product, pentosidine. These crosslinks are known to accumulate in T2DM because of high blood glucose levels and reduced collagen turnover, ultimately compromising the material behavior of collagen in bone and in other tissues. In addition, several outcomes of bone matrix mineralization show that mineral in human T2DM bone is more mature than in nondiabetic controls. As expected with increased mineralization, T2DM bone was stiffer than nondiabetic bone. Remarkably, even though the crosslink and mineralization measures varied between nondiabetic and T2DM bone, compression testing of the T2DM trabecular bone cores showed that they were no more fragile than controls.

The unexpected result that the cores of human femoral neck cancellous bone did not reflect the clinical bone fragility of T2DM patients could be due to many factors. Chief among these is the higher trabecular bone volume, albeit falling short of statistical significance, in T2DM bone cores. Hunt and colleagues⁽⁸⁾ used thoughtful regression models to dissect the effects of bone quality on T2DM bone fragility, independently of the changes in trabecular bone volume. This model succeeds both in identifying which of the variables analyzed in the study impact bone fragility, and in presenting this information in a clinically relevant scenario that stratifies hypothetical T2DM patients at highest risk of fragility fractures. Specifically, the model shows that an increase in trabecular bone volume offers a protective effect for T2DM patients, even with the inferior material quality of the T2DM bone matrix. On the other hand, the model shows how bone quality defects put T2DM patients who have low trabecular bone volume at markedly higher risk of fracture.

The clinical management and variability of the T2DM human patient population may also contribute to the differences between this study and studies of T2DM bone quality in experimental animal models. Hunt and colleagues⁽⁸⁾ wrestle with this challenge in selecting relevant clinical exclusion criteria (ie, thiazolidinedione or teriparatide treatment), and because they chose to study only men, remind the reader that men experience worse health outcomes than women following fracture. Though larger studies will be needed to fully understand these relationships, the observed effects of T2DM on bone quality are independent of age, chronic kidney disease, vitamin D status, and other potential confounders that have previously been shown to impact bone fragility. Whether the medical management of T2DM in these patients may counteract the expected decline in cancellous bone mechanical behavior remains to be determined. Other key factors not examined by this study are the duration of T2DM, the important role of cortical bone in fracture resistance, and the effect of sex differences on bone quality and bone fragility in T2DM.

In summary, the study by Hunt and colleagues⁽⁸⁾ bridges the gap between epidemiologic and experimental analyses of bone fragility in T2DM. With a careful experimental and theoretical analysis of human T2DM bone quality, the investigators elucidate crucial relationships between bone matrix material properties and bone fragility in this clinically relevant human patient population. Further, their findings guide clinical practice by demonstrating the important need to protect bone mass in patients with T2DM. Treatment with antiresorptive or bone anabolic agents could minimize the high risk of fragility fractures in this patient population by counteracting the decline in bone quality. Addressing the outstanding issues in future research will undoubtedly resolve some of the remaining questions and further reconcile the results of this study with the epidemiologic observations of increased bone fragility in T2DM.